Update on the CTTI IND

Safety Assessment and

Communication Project

José M. Vega, MD Vice President, Global Safety Amgen, Inc.

Patrick Archdeacon, MD Medical Officer Office of Medical Policy, CDER/FDA

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Disclaimer

• The opinions and conclusions expressed in

this presentation are those of the presenter

and should not be interpreted as those of the

FDA or of Amgen, Inc.

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First CTTI Project on Serious Adverse

Event Reporting

• In 2009, CTTI undertook the “Improving

Unexpected SAE Reporting to IND

Investigators” project

• Focused on reporting from sponsors to site

investigators

• The project did not primarily focus on

optimizing overall pre-market safety

assessment and communication system

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Recommendations from CTTI Project:

IND Safety Reporting to Site Investigators

• Decrease the volume of uninterpretable and irrelevant

safety reports to investigators

• Supply investigators with meaningful reports that

would improve investigators’ understanding of a drug’s

safety (benefit-risk) profile. This may include:

– Providing only clinically relevant and significant individual adverse

event reports

– Communicating aggregate datasets with context that would allow

generalization and application to various populations

• Engage patient groups to discuss optimal systems for

safety reporting to investigators and patients during

the conduct of a trial; re-evaluate consent language

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FDA published new IND Safety Reporting Rule

to address perceived deficits of existing

expedited reporting rules

• Concurrently with original CTTI project, the new IND Safety Reporting Rule was published September 2010, effective March 28, 2011 – Published guidance on period of enforcement

discretion through September 28, 2011

• Goal – Improve the utility of premarket expedited safety

reports, thereby enhancing human subject protection • Eliminate confusing terminology

• Clarify sponsor and investigator responsibilities

• Eliminate uninformative individual case reports

FDA’s new IND Safety Reporting Rule

• Problems prior to new rule:

– FDA and investigators receiving large numbers of

uninformative IND safety reports

– Sponsors often report serious adverse events as

individual cases that: • Are likely to have been manifestations of the underlying

disease (e.g., mortality or major morbidity)

• Commonly occur in the study population independent of

drug exposure (e.g., strokes or acute myocardial infarctions

in an elderly population)

• Are study endpoints (i.e., the study was evaluating whether

the drug reduced the rate of these events)

– Making a judgment about causality is generally not

possible for these single cases

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FDA’s new IND Safety Reporting Rule

• Report any suspected adverse reaction that is both

serious and unexpected – must meet all three

definitions

– Suspected adverse reaction means any adverse

event for which there is a reasonable possibility that

the drug caused the event

– Unexpected means not listed in the investigator

brochure…

– Serious means results in death, is life-threatening,

hospitalization…

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FDA’s new IND Safety Reporting Rule

• Reporting only if there is evidence to

suggest a causal relationship between the

drug and the adverse event (sponsor

judgment) will mitigate some of the problems

caused by uninformative reports

• However, the new rule raised concerns

among many stakeholders about issues

related to compliance and harmonization

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New CTTI project formed:

IND Safety Assessment and Communication

• Purpose

– To promote responsible oversight of safety for

pre-market drugs consistent with the intent of

FDA’s new IND safety rule

• CTTI’s Executive Committee approved this project

in December 2011

• Team Leaders

– Patrick Archdeacon, FDA

– José Vega, Amgen

– Judy Kramer, Duke

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New CTTI project formed:

IND Safety Assessment and Communication

• Project Plan

– Survey sponsors about current practice

– Summarize anonymized results

– Convene an expert meeting

– Convene a workgroup of biostatisticians from

industry, FDA, and academia

• Work in parallel on methodological issues

– Synthesize output and make recommendations

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Workshop on IND Safety

• Participants:

– Representative from each sponsor who completed

survey

– Biostatistical workgroup members

– FDA

– NIH

– VA

– Academic researchers

• including a representative from Sentinel

– Patient representative

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Workshop on IND Safety

• Meeting Activities

– Review range of current practices in IND safety

assessment and communication

• Present and discuss survey results

– Identify gaps between current practice and an

ultimate system optimized for early detection of valid

safety signals across a drug* development program

– Generate ideas for potential solutions

*This project is limited to consideration of pre-approval safety of drugs and

biologics. This does not diminish the importance of similar considerations

for devices.

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IND Safety Survey Background

• 54 question survey assembled by the

CTTI IND safety assessment and

communication working group

• Completed by 12 of the 14 sponsors who

were solicited for their input

• Two CTTI staffers removed all identifiers

from the collated responses before they

were reviewed by the working group

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Survey Respondents • Amgen

• Astellas

• AstraZeneca

• Bristol-Myers Squibb

• Celgene

• GlaxoSmithKline

• Human Genome

Sciences

• Janssen Research &

Development/ Johnson

& Johnson

• Novartis

• Pfizer

• The Medicines

Company

• Vertex

Meeting participants also included representatives from FDA,

CTTI, NIH, US Department of Veterans Affairs, patient advocates,

and leaders in the field of biostatistics

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Areas of Discussion

I. Organization of Personnel and Data

II. Methods and Processes Developed to

Conduct Aggregate Product Safety

Assessments

III. Confirmation and Escalation of Potential

Safety Signals

IV. Analysis of Blinded Studies

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Major Survey Findings Related to

Organization of Personnel and Data

• 11 out of 12 respondents indicated they use Safety Management Teams (SMTs) to coordinate efforts of individual safety teams related to a given product

• Product data are maintained in parallel safety and clinical databases. Each product typically has a single global safety database, but separate clinical databases for each trial

• Data Monitoring Committees (DMCs) are sometimes relied upon to complement the individual safety team in detecting safety signals, in addition to protecting subject safety in a trial

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Major Survey Findings Related to

Methods for Aggregate Reviews of

Safety Data • Sponsors generally rely on aggregate

analysis of the entire safety population (rather than imbalances across treatment groups) to detect potential safety signals in ongoing blinded trials

• Refinement of potential signals through analysis of the global safety database typically relies on customized queries rather than standardized queries

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Major Survey Findings Related to

Signal Thresholds and Escalations

• 6 of 12 responses specifically stated that individual case reports are still being submitted based on investigator‟s determination of causality

• Clinical judgment rather than quantitative thresholds serve as the basis for decisions

• A range of practices exist regarding thresholds for updating reference safety information versus thresholds for sending IND safety reports based on aggregate data analysis

Major Findings Regarding

Analysis of Blinded Data • 11 of 12 respondents stated that primary review

of safety data for ongoing studies is blinded – except for unblinding of a single reviewer for SAEs

meeting requirements for expedited reporting as individual case reports

• Some sponsors use DMCs to review unblinded or stratified safety data

• A few sponsors indicated experience with internal oversight committees and/or “alternate” safety teams to review aggregate data in unblinded or stratified fashion

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Gaps Identified by Attendees

• Unblinding (n=33)

• Lack of methods for meaningful analysis (n=21)

• Thresholds for reporting (n=19)

• Lack of global harmonization (n=11)

• Expanding role of DMCs (n=4)

• Avoiding false signals (n=3)

• Public perception of new IND rule (n=2)

• MedDRA coding (n=2)

• Increased sponsor resources to assess causality (n=1)

• Planning (n=1)

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Gap 1: Analysis of Blinded Safety Data in

Ongoing Clinical Trials

• Gap: "Inability to unblind treatment status makes it impossible to

assess incremental risk"

• Potential solutions:

–For companies of sufficient size: set up internal safety review

committee in a way that adequately addresses concerns regarding the

potential for bias

–Develop draft guidance from FDA/ICH on use of internal DMCs and/or

allowable unblinding of safety data

–Industry-wide, firewalled third-party consortium

–Possible hybrid internal-external model

–Use of Type 2 DMC (looking at unblinded data across whole

development program)

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Gap 2: Limitations of Current

Methodologies

Potential solutions:

• Elevate safety as study objective to optimize design

• Database solutions:

- Develop unified database to satisfy regulatory

needs with comprehensive clinical dataset

- Have all safety data in an accessible, standard

format so they can be mined and queried

• Create clearinghouse for best practices for complying with

new IND Safety Reporting rule

• Develop best practices for meta-analysis of premarketing

safety data

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Gap 3: International Harmonization

• ICH E2A states:

- “All cases judged by either the reporting HCP or the

sponsor as having reasonable suspected causal

relationship to the medicinal product qualify as ADRs…”

- “The expression „reasonable causal relationship‟ is

meant to convey in general that there are facts

(evidence) or arguments to suggest a causal

relationship.”

- “It may be appropriate to reach agreement with

regulatory authorities in advance concerning serious

events that would be treated as disease-related and not

subject to routine expedited reporting.”

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Gap 4: Difficulty Defining Thresholds

• Most discussed issue other than unblinding,

but fewer solutions proposed

• New reporting rule seems to imply the need

to exercise appropriate clinical judgment –

cause for concern?

• Could one combine the use of DMCs to

monitor “anticipated” events with a

conservative reporting of “unanticipated”

events?

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Next Steps for CTTI IND Safety Assessment

and Communication Project Team

• Publication regarding findings of survey and

meeting discussion

• Report from biostatistical working group on

methodological issues regarding IND safety

rule

• CTTI staff are reviewing SAE reports

previously generated by clinical trials

conducted at the DCRI to field test impact

and practicality of new reporting rule

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Next Steps for Industry to Consider

• Wide implementation of SPERT/CIOMS

VI/ICH E9 recommendations

• Use of SMTs

• Use of PSAPs

• Periodic Aggregate Review

• Planned Safety Meta-Analyses

• Integrated clinical trial safety database

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Next Steps for FDA to Consider

• Additional guidance about handling blinded data in

ongoing trials

• Additional guidance about use of internal oversight

committees and program-level DMCs to assist with

safety assessments

• Develop “anticipated event” concept for assessing

and reporting certain data according to protocol

• Elevate importance of annual report and DSUR

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